Heparin-binding domain of IGFBP-2 in the treatment of metabolic disorders

Abstract

The present technology generally relates to compounds, in particular peptides comprising the heparin-binding domain (HBD) of insulin-like growth factor binding protein-2 (IGFBP-2) for the modulation of metabolic disorders. The present technology also generally relates to uses of such compounds in methods for preventing and/or treating metabolic disorders and in compositions and formulations for such uses.

The invention claimed is: 
     
       1. A method for treatment of a disorder associated with at least one of impaired glucose metabolism, impaired insulin metabolism, and impaired leptin metabolism in a subject, the method comprising: administering to a subject in need thereof a therapeutically effective amount of
 i) a peptide consisting of a fragment of heparin binding domain 1 (HBD1) as set forth in SEQ ID NO: 1, the fragment being 6 to 10 amino acids in length; 
 ii) an analog of a peptide set forth in i), the analog being 6 to 8 amino acids in length and different in sequence from the peptide set forth in i) by 1 or 2 amino acid substitutions, wherein the substitutions are to alanine or are a conservative substitution; 
 iii) an analog of a peptide set forth in i), the analog being 9 or 10 amino acid in length and different in sequence from the peptide set forth in i) by 1, 2 or 3 amino acid substitutions, wherein the substitutions are to alanine or are a conservative substitution; or 
 iv) a pharmaceutically acceptable salt of any one of the peptides set forth in i), ii) and iii). 
 
     
     
       2. The method according to  claim 1 , wherein the disorder is a rare genetic obesity disorder. 
     
     
       3. The method according to  claim 1 , wherein the disorder is syndromic obesity. 
     
     
       4. The method according to  claim 1 , wherein the disorder is a disorder associated with leptin receptor (LEPR) deficiency or with leptin deficiency. 
     
     
       5. The method according to  claim 1 , wherein the disorder is one or more of: hypoglycemia, hyperglycemia, carbohydrate intolerance, glucose intolerance, impaired fasting glucose, impaired glucose tolerance, carbohydrate-lipid metabolism disturbance, hyperinsulinemia, Type IV hyperlipoproteinemia, insulin resistance, diabetes Type I, diabetes Type II, acromegaly, a disorder associated with leptin receptor (LEPR) deficiency, a disorder associated with LEPR mutations, leptin receptor-related monogenic obesity, and syndrome of extreme insulin resistance. 
     
     
       6. The method according to  claim 1 , wherein the peptide is pegylated. 
     
     
       7. The method according to  claim 1 , wherein the peptide is acylated. 
     
     
       8. The method according to  claim 1 , wherein the peptide is cyclic. 
     
     
       9. The method according to  claim 1 , wherein the amino acid substitutions are conservative substitutions. 
     
     
       10. The method according to  claim 1 , wherein the peptide is as set forth in SEQ ID NO: 73. 
     
     
       11. The method according to  claim 1 , wherein the peptide is SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO:13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, or SEQ ID NO: 113. 
     
     
       12. The method according to  claim 1 , wherein said administration is intrathecal, subcutaneous, cutaneous, oral, intravenous, intranasal, intraperitoneal, intramuscular, via an implant, via a matrix, via a gel, or any combination thereof. 
     
     
       13. The method according to  claim 1 , wherein the therapeutically effective amount is from about 0.01 μg/kg to about 100 mg/kg. 
     
     
       14. The method according to  claim 1 , wherein the therapeutically effective amount is from about 0.3 mg/kg to about 3 mg/kg. 
     
     
       15. The method according to  claim 1 , wherein said administering is performed once, twice or three times daily. 
     
     
       16. The method of  claim 1 , wherein the fragment is 6 to 9 amino acids in length and the analog is 6 to 9 amino acid in length.